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Cytokine Phenotypes After the Host's Response During Chronic Lung Inflammation

慢性肺部炎症期间宿主反应后的细胞因子表型

基本信息

批准号：
8197282
负责人：
Steven Lynn Kunkel
金额：
$ 37.49万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197282
关键词：
Animals Autoimmune Diseases Automobile Driving Cell physiology Cells Chronic Chronic Disease Chronic lung disease Clinical Clinical Management Collagen Communicable Diseases Connective Tissue Diseases Dendritic Cells Deterioration Disease Disease Progression Environment Etiology Evolution Experimental Models Fibroblasts Fibrosis Growth Hamman-Rich syndrome Immune Immune Cell Activation Immune response Infection Injury Interleukin-13 Interleukin-4 Interstitial Lung Diseases Investigation Label Laboratories Lead Lesion Lung Lung Inflammation Lung diseases Maintenance Modeling Mus Outcome Pathology Phenotype Predisposition Proteins Research Respiratory physiology Risk Structure of parenchyma of lung Testing Tissues Transforming Growth Factor beta Viral Virus Diseases cytokine design gammaherpesvirus interstitial pathogen research study response

项目摘要

Chronic interstitial lung disease is observed in a variety of disorders, including infectious diseases, autoimmune disorders of connective tissue, and disorders where the etiology is unknown, such as idiopathic pulmonary fibrosis. While the etiology and mechanism of progression of many of these lung disorders are not known, the exacerbated progression of the disease may be dictated by the host responding to a subsequent pathogen superimposed on the initial etiologic agent. This "second hit" triggers a dynamic interaction in the lung between the inciting agent, immune cells, and structural cells of the lung, culminating in fibroblast activation, proliferation and fibrosis. Understanding the mechanisms responsible for the exacerbation and progression of lung disease chronicity and fibrosis are the broad, long-term objectives of this application. We hypothesize that the host's response to a persistent etiologic agent may predispose lung tissue to an environment of reparative and immunoregulatory cytokines, placing the lungs at risk for a viral infection, which mechanistically contributes to disease chronicity by maintaining a unique cytokine phenotype, altering dendritic cell function, and driving fibroblast activation. We have designed experiments to test this hypothesis and determine if the progression and maintenance of chronic lung inflammation are infuenced by the cytokine phenotype and the host's response to a subsequent viral pathogen superimposed on the initial etiologic agent, constituting a "two hit" mechanism for disease progression. We will focus on mechanisms which lead to a minimally fibrotic lung lesion, induced by type 1 cytokines, versus a fibrotic response, induced by type 2 cytokines, and determine their impact on a subsequent challenging with murine gammaherpesvirus (MHV68). Our specific Aims include: 1) To assess the mechanism(s) whereby MHV68 infection alone or superimposed on a polarized cytokine phenotype alters the host response and subsequent lung pathology in experimental models of chronic lung inflammation; 2) To determine the mechanistic contribution of an MHV68-derived gene product on the evolving chronic lung pathology associated with a type 1 or type 2 cytokine tissue phenotype; and 3) To assess the mechanistic contribution of dendritic cell subsets during MHV68 infection to the chronicity and fibrosis of the lung response in animals with developing type 1 or type 2 cytokine phenotypes.

慢性间质性肺病见于多种疾病，包括感染性疾病，